This proposal describes a five-year career development training program designed to lead to an independent academic career in translational neuroscience. Applicant: The applicant holds an M.D. and Ph.D. degree, and has completed specialty training in both Pediatrics and Child Neurology. He has previous experience with human genetics research and developing mouse models of neurologic disease. The career development plan includes a period of mentored research aimed at developing basic neuroscience knowledge and techniques that will greatly enhance his previous training and allow him to develop independence. The training will include learning research techniques and concepts supplemented by didactic training, seminars, lab meetings, journal clubs, national meetings, an advisory committee and meetings with the mentor. The research environment provides the best intellectual environment and the best technology available and gives the applicant the opportunity to be guided in learning powerful laboratory techniques. In addition to developing laboratory skills, the career development plan includes didactic training in grant writing and responsible conduct in research. Research plan: Disorders of function of the post-synaptic protein encoding gene called SHANKs are a new and growing area of scientific interest. Deficiency of SHANK3 causes Phelan-McDermid Syndrome (PMS) which is an autism spectrum disorder. He recently determined that duplications in humans and overexpression in mice also leads to neurodevelopmental symptoms. In this proposal, the applicant aims to investigate the neuronal and molecular mechanisms contributing to the Shank3 overexpression phenotype by genetic and chemo genetic methods to reverse the motor phenotype of these mice. He has used unbiased proteomic approach to investigate the molecular mechanisms driving the overexpression phenotype and identified a novel connection between Shank3 and dopamine receptor signaling.